Overview: The tenOever lab broadly focuses on the molecular interactions between viruses and their host. More specifically, the lab studies how the cell responds to virus. This research encompasses the study of cellular antiviral proteins and small RNAs, of both cellular and virus origin, which contribute to the outcome of infection. The overall objective of this lab is to gain a thorough understanding of the molecular basis of virus pathogenicity in an effort to generate improved vaccines and therapeutics.

Summary of Research Studies: We focus on the interplay between RNA viruses and small RNAs. This research includes the study of microRNAs and virus-derived small RNAs and their role, if any, in the cellular response to infection. In addition, we exploit the small RNA machinery of the cell to control virus tropism, virus synthesis of miRNAs, and the biology of virus-derived small RNAs. Our laboratory uses several techniques to study these RNA-based host-virus interactions including genetic manipulation of both host and pathogen. We are presently working in the following areas.

The cellular response to RNA virus infections: Following viral recognition, the cell responds with the secretion of Type I interferon (IFN-I). This is largely coordinated by cellular kinases which mediate the activation of a number of transcription factors. These transcription factors assemble into a multisubunit complex called the enhanceosome to induce IFN-I transcription. The result of IFN-I signaling is the upregulation of a wide variety of interferon stimulated genes (ISGs). This cellular response functions to render cells resistant to viral infection. We study two kinases critical in the induction and signaling of IFN-I through the genetic manipulation of mice and subsequent in vivo virus infections.

Exploiting microRNAs to control virus tropism: We developed a technology whereby viruses can be engineered to be susceptible to host cell miRNAs. As miRNAs can demonstrate cell- and/or species-specificity, we can use miRNA-mediated targeting to control virus tropism or the level of replication. We use this technology to address fundamental questions about immunology as well develop novel virus vaccines.

The biology of influenza A virus small viral RNAs (svRNA): As a result of miRNA profiling in virus infected cells, we serendipitously discovered a small RNA produced by influenza A virus. While not a miRNA, this small viral RNA (svRNA) accumulates to >10000 copies per cell and has a significant impact on the virus’ replicative cycle. This area of research presently focuses on the biogenesis and molecular function of svRNA.

Non-canononical cytoplasmic production of viral miRNAs: We recently determined that viruses could be engineered to produce functional microRNAs. While this was not surprising for viruses such as influenza A virus, which replicates in the nucleus, we also found cytoplasmic viruses were capable of miRNA synthesis. This research focus is aimed at determining the molecular basis underlying this phenomenon.

Perez JT, Varble A, Sachidanandam R, Zlatev I, Manoharan M, García-Sastre A, tenOever BR. Influenza A virus-generated small RNAs regulate the switch from transcription to replication. Proceedings of the National Academy of Sciences of the United States of America 2010 Jun; 107(25).

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